Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

Serdal Gungor; Yavuz Oktay; Semra Hiz; Álvaro Aranguren-Ibáñez; Ipek Kalafatcilar; Ahmet Yaramis; Ezgi Karaca; Uluc Yis; Ece Sonmezler; Burcu Ekinci; Mahmut Aslan; Elmasnur Yilmaz; Bilge Özgör; Sunitha Balaraju; Nora Szabo; Steven Laurie; Sergi Beltran; Daniel G MacArthur; Denisa Hathazi; Ana Töpf; Andreas Roos; Hanns Lochmuller; Isabelle Vernos; Rita Horvath

doi:10.1016/j.isci.2020.101948

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

iScience. 2020 Dec 30;24(1):101948. doi: 10.1016/j.isci.2020.101948. eCollection 2021 Jan 22.

Authors

Serdal Gungor¹, Yavuz Oktay^{2

3}, Semra Hiz^{2

4}, Álvaro Aranguren-Ibáñez⁵, Ipek Kalafatcilar^{2

4}, Ahmet Yaramis⁶, Ezgi Karaca^{2

3}, Uluc Yis⁴, Ece Sonmezler², Burcu Ekinci², Mahmut Aslan⁴, Elmasnur Yilmaz², Bilge Özgör¹, Sunitha Balaraju^{7

8}, Nora Szabo^{8

9}, Steven Laurie¹⁰, Sergi Beltran¹⁰, Daniel G MacArthur^{11

12}, Denisa Hathazi⁸, Ana Töpf⁷, Andreas Roos¹³, Hanns Lochmuller¹⁴, Isabelle Vernos^{5

15

16}, Rita Horvath⁷

Affiliations

¹ Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, Turkey.
² Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey.
³ Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University and Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey.
⁴ Dokuz Eylul University, Faculty of Medicine, Department of Pediatric Neurology Izmir, Turkey.
⁵ Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
⁶ Pediatric Neurology Clinic, Private Office, Diyarbakir, Turkey.
⁷ John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.
⁸ Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Robinson Way, Cambridge CB2 0PY, UK.
⁹ Budai Children Hospital, Észak-Közép-budai Centrum, Új Szent János Kórház és Szakrendelő, Budapest, Hungary.
¹⁰ CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
¹¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Leibniz Institut für Analytische Wissenschaften, ISAS, Dortmund, Germany & Pediatric Neurology, University Hospital, University of Duisburg-Essen, Faculty of Medicine, Essen, Germany.
¹⁴ Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, the Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
¹⁵ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹⁶ Institució Catalana de Recerca i Estudis Avançats (ICREA), Spain.

Abstract

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

Keywords: Biological Sciences; Clinical Neuroscience; Molecular Neuroscience; Neuroscience; Protemics; Systems Biology.

Abstract

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